The overall goal of this grant proposal entitled Biogenesis of HDL Through Cholesterol Efflux and ApoA-I Structural Reorganization is to define a novel role for Procollagen C Proteinase Enhancer 2 (PCPE2) in the formation and function of HDL as it relates to the progression of atherosclerosis. By 2025, worldwide death due to atherosclerosis and associated complications is projected to surpass that of every major disease, including cancer, infection and trauma. The total cost of atherosclerosis-related diseases in the U.S. alone is estimated to be $286 billion annually. After statins, there is no break-through strategy in the pipeline to combat this deadly global disease. Our laboratory has studied the role of HDL apoA-I in atherosclerosis for the last 25 years and have shown, as others have, that apoA-I is an important modulator of atherosclerosis. Despite this clarity, all attempts to reduce atherosclerosis in humans by pharmacologically raising HDL levels have failed. Many believe this is a result of increasing plasma HDL concentrations without increasing or raising its functionality. Therefore, we expect to show that PCPE2 enhances HDL functionality at both the level of cholesterol efflux, as well as, its role in HDL turnover and catabolism. To do this we have crafted three specific aims.
Specific Aim 1 : To investigate molecular transitions of specific apoA-I helical domains responsible for promoting the biogenesis of nascent HDL (nHDL).
Specific Aim 2 : Delineate the role of the accessory protein, PCPE2 in nHDL assembly by examining interactions between these two proteins and to determine how this interaction affects the opening of lipid-free apoA-I.
Specific Aim 3. Examine the role PCPE2 plays in mediating HDL metabolism and in the development of atherosclerosis in a newly created LDLr- /-, PCPE2-/- mouse model. At the end of the project, we expect that PCPE2 will be found to be a novel molecule mechanistically involved in increasing HDL functionality in humans providing a new strategy for combating atherosclerosis.

Public Health Relevance

Atherosclerosis and myocardial infarction are the leading cause of morbidity in the US. The relationship between atherosclerosis and cholesterol homeostasis is important in understanding and preventing this disease process. Our studies are relevant because they will focus on the pathway(s) that regulates tissue cholesterol balance through the formation of nascent high density lipoprotein particles via ABCA1. Therefore, our studies will provide insight into how HDL functions to protect against the progression of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127649-03
Application #
9246568
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Liu, Lijuan
Project Start
2015-04-01
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
$537,006
Indirect Cost
$165,177
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Cooke, Allison L; Morris, Jamie; Melchior, John T et al. (2018) A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. J Lipid Res 59:1244-1255
Goldberg, Ira J; Reue, Karen; Abumrad, Nada A et al. (2018) Deciphering the Role of Lipid Droplets in Cardiovascular Disease: A Report From the 2017 National Heart, Lung, and Blood Institute Workshop. Circulation 138:305-315
Gaddis, Dalia E; Padgett, Lindsey E; Wu, Runpei et al. (2018) Apolipoprotein AI prevents regulatory to follicular helper T cell switching during atherosclerosis. Nat Commun 9:1095
Milasan, Andreea; Jean, Gabriel; Dallaire, Fran├žois et al. (2017) Apolipoprotein A-I Modulates Atherosclerosis Through Lymphatic Vessel-Dependent Mechanisms in Mice. J Am Heart Assoc 6:
Melchior, John T; Walker, Ryan G; Cooke, Allison L et al. (2017) A consensus model of human apolipoprotein A-I in its monomeric and lipid-free state. Nat Struct Mol Biol 24:1093-1099
Williams, Jesse W; Elvington, Andrew; Ivanov, Stoyan et al. (2017) Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood. Circ Res 121:662-676
Lee, Mi-Hye; Appleton, Kathryn M; El-Shewy, Hesham M et al. (2017) S1P in HDL promotes interaction between SR-BI and S1PR1 and activates S1PR1-mediated biological functions: calcium flux and S1PR1 internalization. J Lipid Res 58:325-338
Sorci-Thomas, Mary G; Thomas, Michael J (2017) AIBP, NAXE, and Angiogenesis: What's in a Name? Circ Res 120:1690-1691
Hoekstra, Menno; Sorci-Thomas, Mary (2017) Rediscovering scavenger receptor type BI: surprising new roles for the HDL receptor. Curr Opin Lipidol 28:255-260
Sorci-Thomas, Mary G; Thomas, Michael J (2017) Anti-inflammatory liaisons: T regulatory cells and HDL. J Lipid Res 58:1491-1492

Showing the most recent 10 out of 20 publications